The overall goal of our SCOR is to increase our understanding of normal airway biology and the pathogenesis of cystic fibrosis (CF) airway disease, and to use that knowledge to develop new therapies. The strength of our SCOR is demonstrated by the impact of our past contributions, the interactions between our project leaders, their commitment to CF research, and the quality of our current proposal. The SCOR consists of four interrelated research projects focused on CFTR and airway defenses against bacterial infection. Loss of the CFTR C1- channel disrupts airway epithelial electrolyte transport, contributing directly to disease pathogenesis. In Project 1, Drs. Welsh and Ostedgaard use powerful new approaches to learn how the cytoplasmic domains of CFTR stimulate channel activity and to test the novel hypothesis that CFTR has adenylate kinase activity that controls channel gating. The chronic airway infections that are a hallmark of CF indicate that loss of CFTR causes a local host defense defect. In Project 2, Drs. McCray, Schutte and Singh investigate the role that airway surface liquid (ASL) peptides and proteins play in airway defense. They pursue their discovery of many new antibacterial and potentially anti-inflammatory ASL factors to elucidate how these contribute to the innate immune system. The discovery that lowering ionic strength augments the in vitro activity of nearly all ASL antimicrobial factors has led Drs. Zabner, Singh and Brogden in Project 4 to test the compelling hypothesis that reducing ASL salt concentrations in vivo, by administering the non-ionic osmolyte xylitol will prevent or slow the progression of CF airway disease. They begin testing this hypothesis in mice, sheep and humans. Our ability to evaluate such therapeutic strategies and to test hypotheses about the pathogenesis of CF lung disease has been hampered by the lack of an animal model that reproduces the airway and submucosal gland phenotype of people with CF. Based on substantial preliminary data, Dr. Engelhardt in Project 3, tackles this problem with an ambitious plan to clone a CF ferret. The SCOR benefits from outstanding support by the In Vitro Models and Cell Culture Core, as well as the Administrative Core. As a whole, this SCOR will give us unprecedented insight into CF airway dysfunction and hasten the development of new treatments for this devastating disease.